DESCRIPTION: (Verbatim from the Applicant's Abstract) The normal spinal cord is a complex community of interacting and interdependent cells. With traumatic spinal cord injury (SCI) this cellular organization is profoundly disturbed and secondary injury mechanisms are triggered that act to exacerbate the loss of cells and functional capacity. Substantial progress has been made in identifying secondary injury mechanisms that contribute to loss of white matter after SCI. Specifically, data has been generated to suggest that tetrodotoxin (TTX)-sensitive Na+ channels play an important role in secondary injury and acute loss of white matter axons. However, the PI also has data implicating ionotropic AMPA and/or kainate receptors in mediating oligodendrocyte cell death and consequently abnormal myelination of surviving axons after incomplete SCI. In the new project period these hypotheses will be tested using a standardized rat model of clinically-relevant contusive SCI. Using electron microscopy and quantitative morphological analysis, they will determine whether: a) acute treatment with TTX will permanently preserve axons 'at risk' after SCI and b) Na channel blockers other than TTX are effective in reducing axonal loss. With immunocytochemistry and in situ hybridization they will determine how treatment with Na channel blockers affects glial loss, the proliferation of glial precursor cells, and myelin gene expression in the injured spinal cord. They will use selective antagonists of specific glutamate receptors to determine their effect on: a) survival of white matter oligodendrocytes acutely over the first 24 h after injury; and b) the myelination of spared axons chronically after SCI. Based on these results they will investigate a third hypothesis: the combination of an acute Na channel blocker and an acute AMPA and/or kainate receptor antagonist will produce an additive effect in reducing chronic white matter pathology and functional deficits after SCI. It is their goal to provide insights to ways of enhancing tissue sparing and functional recovery after SCI.